NO145436B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMINES - Google Patents

Description

The invention relates to analogue methods for the production of new therapeutically active amines with g-receptor blocking action.

The invention relates to an analogous method for the production of therapeutically active amines of formula

wherein R"^ means methyl, ethyl, propyl, cyano, cyanomethyl or CH3OCH2CH2NHCOCH20-, R<2> and R<3> are the same or different and each means hydrogen, hydroxy, methoxy or hydroxymethyl provided that R 2 and R^ ~* > not both mean hydrogen, as R 2 and/' or F? means hydroxy, hydrogen or hydroxymethyl when R<1 >means methyl, the method being characterized in that

a) a compound of formula II

in which. R1 has the meaning given above, X<1> means a hydroxy group and Z is a reactive, esterified hydroxy group, or X"*" or Z together form an epoxy group, reacted with an amine of formula

wherein R and R^ 1 have the meaning indicated above, or

b) a compound according to formula III

in which R"1" has the meaning given above, is reacted with a compound according to formula

in which R 2 , R "5 and Z have the meaning indicated above, or

c) a compound according to formula IV

in which R"*" has the meaning given above, is replaced by a

compound of formula V

12" 5

in which Z, X , R and R have the meaning stated above, or

d) a compound of formula IV

in which R"*" has the meaning stated above, is traded with

a compound of formula VI

in which R 2 and r 3 have the above meaning,

or

1 2

e) from a compound according to formula I, in which R , R

and R<3> has the meaning indicated above, and which compound

has a cleavable residue bound to the amino group and/or the hydroxy groups, this/these residue(s) are cleaved off, or

f) a Schiff's base according to formula VIII or IX

or a cyclic tautomer of formula X corresponding to the compound of formula IX

12 3

in which R , R , R , n and X have the meaning given above, since the compounds IX and X can be present at the same time, reduced or

g) in a compound of formula XI

12 3

where R , R and R have the above meaning, the oxo group is reduced to a hydroxy group,

h) in a compound according to formula XII

2 3.

where R and R have the same meaning as stated above and wherein

2 1

X is a residue transferable to R with the same meaning

2. 1

as above, X is transferred to R , or

i) in a compound according to formula Va

in which R"'', n and Z have the meaning indicated above, is reacted with a compound according to formula IVa

wherein R and R have the above meaning and, if desired, aqueous free bases are transferred in their therapeutically acceptable salt or formed salt is transferred in their free bases.

The new compounds have valuable pharmacological properties. Thus, they block cardio-8 receptors, which is shown on determination of the antagonism of tachycardia after an intravenous injection of 0.5 ug/kg of d/l-isoproterenol sulfate in anesthetized cat an intravenous dose of 0.002-2 mg/kg. They also block the vascular 3-receptors as shown by determination of antagonism of vasodilatation after an intravenous injection of 0.5 Mg/kg of d/l-isoproterenol sulfate in anesthetized cat at an intravenous dose of 0.002-2 mg/kg or more. The obstacles also have stimulating properties on β-receptors, i.e. they show intrinsic activity. This property is particularly pronounced regarding vascular g-receptors, which cause dilatation of peripheral blood vessels.

The new compounds can be used in treatment

of arrythma, angina pectoris and hypertension. The peripheral vasodilatation is particularly valuable for the two latter indications. They can also be used as intermediates in the production of other valuable pharmaceutical products.

Salt-forming acids can be used in the preparation of therapeutically tolerable salts of the compounds. These are: hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid,' propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-amino-benzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acid, methionine, tryptophan, lysine or arginine .

The substances are intended for administration orally or parenterally for acute and chronic treatment of the above-mentioned cardiovascular irregularities.

The biological effect of the new compounds

has been investigated and the various tests that are carried out will be discussed below.

The new compounds are produced according to methods known per se. A compound of formula II

in which R has the above meaning, X"<*>" means a hydroxy group, Z is a reactive, esterified hydroxy group or X^ and Z together means an epoxy group, reacted with an amine of formula

2 3

wherein R , R , n and X have the above meanings.

A reactive esterified hydroxy group is in particular a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or a strong organic sulphonic acid, e.g. benzenesulfonic acid, 4-chromobenzenesulfonic acid or 4-toluenesulfonic acid. Thus Z preferably means chlorine, bromine or iodine.

The turnover is carried out in the usual way. When using a reactive ester as a starting material, the preparation preferably takes place in the presence of a base condensation agent and/or with an excess of an amine. Suitable basic condensing agents are e.g. alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as potassium carbonate and alkali metal alcoholates such as sodium methylate, potassium ethylate and potassium tert.-butylate.

The reaction is carried out in an alkanol with 1 to 4 carbon atoms by refluxing the reaction component in the solvent for a time long enough to form the compound of formula 1, usually 1 to 12 hours.

Furthermore, a compound of formula III is reacted

wherein R<1> has the above meaning with a compound of formula

wherein R 2 , R <3> and Z have the above meaning.

This reaction is carried out in the usual way, preferably in the presence of a basic condensation agent and/or an excess of an amine. Suitable basic condensation agents are e.g. alkali alcoholates, preferably sodium or potassium alcoholate, or also alkali carbonates such as sodium or potassium carbonate.

The reaction is carried out in an alkanol with 1 to 3 carbon atoms in an autoclave heated to 100 to 130°C for 5 to 15 hours.

Furthermore, a compound of formula IV is reacted

wherein R"<*>" has the above meaning with a compound of formula V,

12

wherein Z, X, R and r3 have the above meaning.

This turnover is carried out in the usual way. In cases where reactive esters are used as starting material, the compound of formula IV can conveniently be used in the form of the metal phenolate as an alkali metal phenolate, preferably sodium phenolate, or one works in the presence of an acid-binding agent, preferably a condensation agent, which can form a salt of the compound of formula IV as alkali metal alcoholate.

The reaction is carried out in an alkanol with 1 to 3 carbon atoms in an autoclave heated to 80 to 100°c for 5 to 15 hours.

Furthermore, a compound of formula Va is reacted

wherein R 1 , Z and n have the above meaning, with a compound of formula IVa

wherein R 2 and R 3 have the above meaning.

The turnover is expressed in the same way as the turnover between the compounds of formula IV and V above.

Furthermore, a compound of formula IV is reacted

wherein R"*" has the above meaning, with a compound of formula VI

wherein R2 and R3 have the above meaning.

This turnover is carried out in the usual way. Thus, the reaction is carried out under alkaline conditions in a suitable solvent such as benzyl alcohol by boiling the reaction mixture for a few hours. Thereby, the phenol is primarily transferred to its metal phenolate as an alkali metal phenolate before being added to the acetidinol of formula VI.

Furthermore, from a compound according to formula I,

1 ? 3

in which R , R" and R have the above meaning, and which compound has a cleavable residue bound to the amino group and/or the hydroxy group, this/these residues are cleaved off.

Such cleaved residues are especially those that can be cleaved by solvolysis, reduction, pyrolysis or fermentation.

Residues that can be split off by solvolysis are preferably residues that can be split off by hydrolysis or ammonolysis.

Residues that can be split off by means of hydrolysis are e.g. an acyl residue, if, when present, is functionally varied carboxy groups, e.g. oxycarbonyl residues, such as alkoxycarbonyl residues, e.g. tert-butoxycarbonyl radical or ethoxycarbonyl radical, aralkoxycarbonyl radical such as phenyl-lower-alkoxycarbonyl radical, e.g. a carbobenzyloxy acid residue, halocarbonyl residue, e.g. a chlorocarbon residue, further arylsulfonyl residue such as toluenesulfonyl or bromobenzenesulfonyl residue and optionally as halogenated, as fluorinated lower alkanoyl residue such as formyl, acetyl or trifluoroacetyl residue or a benzyl residue of cyano groups or silyl residues, such as trimethylsilyl residue.

Of the above-mentioned residues which are present at the hydroxy groups, which residues can be split off by hydrolysis, the oxycarbonyl residue and the lower alkanoyl residues or the benzoyl residue are preferably used.

In addition to the above, double-bonded residues, which can be split off at the amino group by hydrolysis, are used, e.g. alkylidene or benzylidene residue or a phosphorylidene group such as a triphenylphosphorylidene group,

as the nitrogen atom then acquires a positive charge.

Residues that can be split off at the hydroxy group and the amino group by hydrolysis are further divalent residues which, in some cases, substitute the methylene. As substituents on the methylene residue, any organic residue can be used, as it does not play any role in the hydrolysis which compounds are substituents in the methylene residue. As methylene substituents, e.g. aliphatic or aromatic residues, such as alkyl,

as mentioned above, aryl e.g. phenyl or pyridyl can be used. The hydrolysis can be carried out in any suitable manner in a basic or preferably in an acidic medium.

The hydrolyses are carried out in an analogous way,

e.g. in the presence of a hydrolyzing agent,

e.g. in the presence of an acidic agent, such as diluting mineral acids, such as sulfuric acid or hydrohalic acid, or in the presence of basic agents such as

e.g. alkali metal hydroxides, such as sodium hydroxide. Oxycarbonyl residues, arylsulfonyl residues and cyano groups can be cleaved in a suitable manner by means of acidic agents, such as by means of a hydrohalic acid, especially hydrobromic acid. Preferably, the separation can take place using diluted hydrobromic acid, possibly in a mixture with acetic acid. Cyano groups are preferably split off using hydrobromic acid at an elevated temperature such as in boiling hydrobromic acid according to the "bromocyano method"

(v. Braun). Furthermore, can e.g. a tert.-butoxycarbonyl residue is cleaved off under anhydrous conditions by treatment with a suitable acid, such as trifluoroacetic acid. Acidic agents are preferably used in a hydrolysis of the compounds of formula VI.

Residues that can be split off by ammonolysis are especially the halogenocarbonyl residues, such as chlorocarbonyl residues. The ammonolysis can be carried out in the usual way, e.g. using

an amine, containing at least one hydrogen atom bonded to the nitrogen atom, such as a mono- or di-alkylamine, e.g. methylamine or dimethylamine, or especially ammonia, preferably at an elevated temperature. Instead of ammonia, an agent that gives ammonia such as hexamethylenetetramine can be used.

Residues that can be split off by means of reduction are e.g. an α-arylalkyl radical, such as a benzyl radical or an α-aralkoxycarbonyl radical, such as a benzyloxycarbonyl radical, which can usually be cleaved by hydrogenolysis, especially by catalytically activated hydrogen, such as by hydrogen in the presence of hydrogenating catalysts, e.g. Raney nickel. Further residues that can be cleaved by hydrogenolysis are 2-halogeno alkoxycarbonyl residues such as 2,2,2-trichloroethoxycarbonyl residues or 2-iodoethoxy or 2,2,2-tribromethoxycarbonyl residues, which can be cleaved

in the usual way, expediently by means of a metallic reduction (so-called nascent hydrogen). Nascent hydrogen can be obtained by the action of metal or metal alloys, such as amalgam, on compounds that give hydrogen such as carboxylic acids, alcohols or water, zinc or zinc alloys being used in particular together with acetic acid. Hydrogenolysis of 2-halo-alkoxycarbonyl residues can also take place using

tes chromium or chromium (II) compounds such as chromium (II) chloride or chromium (II) acetate.

A residue that can be offset by reduction can also be

an arylsulfonyl group such as a toluenesulfonyl group, which is cleaved off in the usual way by reduction, using nascent hydrogen, e.g. by means of an alkali metal such as lithium or sodium in liquid ammonia and conveniently can be cleaved from a nitrogen atom. To carry out the reduction, it must be ensured that other reducing groups are not affected.

Residues cleavable by means of pyrolysis, especially residues cleavable from the nitrogen atom are in some cases substituted, possibly unsubstituted carbamoyl groups. Suitable substituents are e.g. lower alkyl or aryl lower alkyl such as methyl or benzyl or aryl, such as phenyl, the pyrolysis is carried out in the usual way, taking into account other thermally exposed groups.

Residues cleavable by fermentation, in particular residues cleavable from the nitrogen atom are in some cases substituted, but preferably unsubstituted carbamoyl groups. Suitable substituents are e.g. lower alkyl or aryl lower alkyl, such as methyl or benzyl, or aryl such as phenyl. The fermentation is carried out in the usual way, e.g. with the help of the enzyme urease or soybean extract at approx. 20°C or slightly elevated temperature.

Furthermore, a Ship base with formula VIII or

IX

or a cyclic tautomer corresponding to formula IX or formula X

is reduced, in which R^, R<2> and R3 have the above-mentioned meaning and since the compounds of formula IX and X can also exist together. This reduction is carried out in the usual way, e.g. using a dilett metal hydride, such as sodium borohydride, lithium aluminum hydride, using a hydride such as borane with formic acid, or by means of a catalytic hydrogenation, such as with hydrogen in the presence of Raney nickel. During the reduction, care must be taken that other groups are not affected.

Furthermore, the group in the connection with formula can also

XT

wherein R"<*>", R^ and R 3 have the above meaning, is reduced to a hydroxy group. This reduction is carried out in the usual way, in particular by using a di-light metal hydride, as mentioned above, or according to the "Meerwein-Pondorf-Verley method" or a modification thereof, by appropriately using an alcohol as a reaction component and a solvent, as isopropanol and a metal alkanolate is used, as metal iso-

propanolate, e.g. aluminum isopropanolate.

Furthermore, in a connection with formula XII

wherein R and R 3 have the above meaning and where x 2 is a residue capable of being transferred to a residue R 1 , \ 2 is transferred to Ri.

Furthermore, the oxo group in a compound corresponding to those of formula I and which carries an oxo group at the carbon atom bound to a nitrogen atom can be reduced by two hydrogen atoms.

Said compounds are e.g. those with a formula

XIII

in which R 1 , R 2 and Rj5 have the above meaning.

The reduction can be carried out according to the above-mentioned method, using complex metal hydrides, e.g. lithium aluminum hydride or diisobutylaluminum hydride. Conveniently, the reaction takes place in an inert solvent such as an ether, e.g. diethyl ether or tetrahydrofuran.

In the usual way, the substituents can vary from the compounds obtained within the end products, as well as the compounds obtained can be introduced, split off or transferred into other end products in the usual way.

Depending on the reaction conditions and the starting material, the end product is obtained either in free form or in the form of acid addition salts, which are included within the scope of the invention. Thus, e.g. basic, neutral or mixed salts are obtained as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds can be transferred in a manner known per se into free compounds, using basic agents such as alkali or ion exchangers. On the other hand, the free bases formed can form salts with organic or inorganic acids. In the preparation of acid addition salts, such acids are preferably used which form suitable therapeutically tolerable salts. Such acids are e.g. hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, phenylacetic acid . methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds such as e.g. picrates can serve as cleaning agents or the free bases that are formed as free bases are transferred into salts, these are separated and the bases are then freed from the salts again. According to the close relationship between the new compounds in free form and in the form of their salts, the corresponding salts are also covered by the free compounds.

Such starting materials are preferably used for carrying out the conversion according to the invention which leads to groups of end products, which are preferably suitable and especially for the mentioned and preferred end products.

The starting materials are known or can,

if they are new, they are obtained by methods known per se.

In clinical use, the connection is administered

according to the invention normally orally, rectally or by injection in the form of a pharmaceutical preparation containing an active compound, either as a free base or a pharmaceutically acceptable, non-toxic acid addition salt, e.g. hydrochloride lactate, acetate, sulfamate

or the like in combination with a pharmaceutical carrier.

The mention of the new compounds according to the invention refers here to either the free amine base or the acid addition salt of the free base, even if the compound is generally or specifically described, provided that the meaning in which such terms are used, e.g. in the examples, does not correspond to the broad meaning it should have. The carrier may be a solid, semi-solid or liquid diluent or a capsule. These pharmaceutical preparations are further subject of the invention. Generally, the amount of active compound is between Q.1 and 99% by weight of the preparation, suitably between 0.5 and 20% by weight in the preparations for injection and between 2 and 50% by weight in the preparations for oral administration.

The daily dose of the active substance varies and depends on the type of administration, but usually it is 100 to 400 mg/day active substance for oral administration and 5 to 20 mg/day for intravenous administration.

The invention will be explained in more detail with the help of some examples.

§^§S5!E§i_i_r_5!^S?}§'£iiii2S_§Y_2zI2i( ii::l2y.droxy.f enoxy.2:§£Y.i:: amino]-l-o-met^lphenox^-groganol^^ .

2.5 g of 1,2-epoxy-3-o-methylphenoxypropane was mixed with 1.5 g of 2-(4-hydroxyphenoxy)-ethylamine and 25 mg of isopropanol and the mixture refluxed for 1.5 hours. The solution was evaporated in vacuo. The base thus formed was dissolved in acetone and the hydrochloride precipitated using HCl in ether. The hydrochloride was filtered off and washed with acetonitrile. The yield of 3~[2-(4-hydroxyphenoxy)-ethylamine]-1-o-methylphenoxy-propanol-2 was 1.5 g. Melting point 150°C (HC1). The structure was determined by NMR.

Eczema<e>l_2

3-[2-(2-Hydroxyphenoxy)-ethylamino]-1-o-methyl-phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-(o-methyl)-phenoxy-propane and 2-(2-phenoxy-hydroxy)-ethylamine as starting material. Melting point of its

hydrochloride is 80°C. The structure was determined by NMR and equivalent weight.

Eczema gel_3

3-[2-(2-methoxyphenoxy)-ethylamino]-1-o-methyl-phenoxy-propanol-2 • was prepared according to example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2-(2-methoxy -phenoxy)-ethylamine as starting material. The tartrate's melting point is 91°C. The structure was determined by NMR and equivalent weight.

Example_el_4

3-[2-(i(-Methoxyphenoxy)-ethylamino]-1-o-methyl-phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2-(4 -methoxyphenyl)ethylamine as starting material The hydrochloride melted at 168°C.

Eczema gel_5

3~[2-(3,4-dimethoxyphenoxy)-ethylamino]-1-o-methyl-phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy:y-3-o-methylphenoxypropane and 2-( 3, 4-dimethoxy-phenoxy-ethylamine as starting material The hydrochloride melted at 160°C.

Eczema gel_6

3-[2-(4-Hydroxyphenoxy)-ethylamino]-1-o-n-propyl-phenoxy-y-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-n-propylphenoxypropane and 2-(4- hydroxy-phenoxy)-ethylamine as starting material. The melting point of the hydrochloride is 135°C

Example_gl_ 1

3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-propyl-phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3~o-n-propylphenoxypropane and 2-(4-hydroxy- phenoxy)-ethylamine as starting material. Melting point: 168°C (neutral oxalate).

Example_el_8

3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-cyano-phenoxy-propanol-2 was prepared according to example 1 using

Else of 1,2-epoxy-3~o-cyanophenoxypropane and 2-(4-hydroxy-phenoxy)-ethylamine as starting material. The tartrate melted at 52°C.

Example_el_9

3-[2-(4-hydroxymethylphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3_o-cyanophenoxypropane and 2-(4-hydroxymethylphenoxy) -ethylamino as starting material Melting point 86°C (base).

Example 10

3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-ethyl-phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-ethylphenoxypropane and 2-(4-hydroxy- Phenoxyethylamine as starting material Melting point 140°C (HCl).

Example 11

3-[2-(4-Methoxyphenoxy)-ethylamino]-1-o-cyano-phenoxypropanol-2 was prepared according to Example 1 from 1,2-epoxy-3-o-cyanophenoxypropane and 2-(4-methoxyphenoxy)-ethylamine . Melting point 134°C (HCl).

Example_el_12

3-[2-(2-hydroxyphenoxy)-ethylamino]-1-o-cyano-phenoxy-propanol-2 was prepared according to Example 1 from 1,2-epoxy-3-o-cyanophenoxypropane and 2-(2-hydroxyphenoxy)-ethyl - county Melting point l8l°C (HCl).

Example_el_13

3-[2-(4-hydroxy-3-methoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 was prepared according to Example 1

of 1,2-epoxy-3-o-cyanophenoxypropane and 2-(4-hydroxy-3_meth^oxyphenoxy1-ethylamine. Melting point 78°C (HCl).

Eczema gel_l4

3-[2-(3,5-dimethoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 was prepared according to Example 1 from 1,2-epoxy-3_o-cyanophenoxypropane and 2-(3,5-dimethoxyphenoxy )-ethylamine. Melting point 159°C (HCl).

Eczema gel_15

3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-hydroxy-methylphenoxy-propanol-2 was prepared according to Example 1 from 1,2-epoxy-3-o-hydroxymethylphenoxypropane and 2-(4-hydroxyphenoxy )-ethylamine. Melting point 68°C (citrate).

Exemgel l§__(method_i2

25.4 g of 2-[3_o-cyanophenoxy-2-hydroxypropylamino]-ethyl chloride, 10.8 g of 4-hydroxyphenol and 20.7 g of potassium carbonate are refluxed for 8 hours with stirring in acetonitrile. The reaction mixture is then filtered, evaporated, acidified with HCl and extracted with ether. The aqueous phase was made alkaline and re-extracted with ether. The ether phase was dried over MgSO 4 and evaporated to give the base of 1[2-(4-hydroxyphenoxy)-ethylamino]-3-o-cyanophenoxypropanol-2. Melting point 52°C (tartrate). Yield 13.7 g (42% of the theoretical). Example_el_17_.(method_b+e2 10 g of o-methylphenyl glycidyl ether in 100 ml of ethanol was saturated with gaseous ammonia and the mixture heated in an autoclave on a boiling water bath for 4 hours. The solvent was evaporated and the residue dissolved in ethyl acetate, whereupon HC1 gas was introduced. The hydrochloride of 1-amino-3-(o-methylphenoxy)-propanol-2 thereby precipitated and was filtered off and dissolved in 50 ml of ethanol to which 2-(4-methoxymethoxy)-phenoxy-ethyl chloride and 15 g of KgCO had been added ^. The mixture was heated in an autoclave at 130°C for 10 hours, after which the solvent was evaporated and the residue treated with 100 ml of 2N HCl for 1 hour at room temperature. The aqueous phase was made alkaline with ammonia and extracted with ethyl acetate. The solvent phase was dried over K0CO^ to give 1-[2-(4-hydroxyphenoxy)-ethylamino]-3-(o-methylphenoxy)-propanol-2 The base formed was converted to its hydrochloride 1-[2-(4 -hydroxy-syphenoxy)-ethylamino]-3-(o-methylphenoxy)-propanol-2-hydrochloride Melting point 150°C.

Exemgel_l8_ (_method_c+e)

2.4 g of Na were dissolved in 100 ml of ethanol, after which 10.8 g of o-methylphenol and then 22.9 g of 1-[2-(4-meth-oxymethoxy)-phenoxyethylamino]-3-chloropropanol-2 were added . The mixture

was heated in an autoclave on a boiling water bath for 10 hours. It was then filtered and the filtrate evaporated to dryness. The residue was treated with 2N HCl for 1 hour at room temperature and extracted with ether, after which the aqueous phase was made alkaline with ammonia and extracted with ether. The ether phase was dried over MgSO 4 and 1-[2-(hydroxy)-phenoxy-ethylamino]-3-(o-methylphenoxy}-propanol-2 was obtained and converted to the hydrochloride and isolated. Melting point 150°C.

Ex.emp_el_19_ (.method_d2

0.116 mol of o-methylphenol was mixed with 0.080 mol of 1-[2-(4-methoxymethoxyphenoxy)-ethyl]-3-acetidinol, 0.500 mol of henzyl alcohol and 0.003 mol of KOH. The mixture was refluxed with stirring for 6 hours at 140°C and then cooled and extracted with 2N HCl. The water phase was allowed to stand for 1 hour at room temperature, after which it was made alkaline and finally extracted with chloroform. After drying and evaporation, the residue was dissolved in ether and HCl in ether was added to the solution. The hydrochloride was filtered off and washed with acetone. The hydrochloride of 3-t2-(4-hydroxyphenoxy)-ethylamino]-1-(o-methylphenoxy).-propanol-2 melted at 150°C.

Eksemgel_20_(method_f)

According to Example 17 above, 1-amino-3-(o-methylphenoxy}-propanol-2 was prepared. 5 g of this compound was dissolved in 50 ml of methanol and 15 g of 4-hydroxyphenoxy-acetaldehyde was added, resulting in 3- [2-(4-Hydroxy-phenoxy)-ethylimino]-1-o-methylphenoxy-propanol-2. The solution was cooled to 0°C and at this temperature 5 g of sodium borohydride was added gradually, as the imino compound was reduced. The temperature then reached rise to room temperature and after 1 hour 150 ml of water was added and the total solution extracted with ether. The ether phase was dried over MgSOjj°S evaporated. The residue was converted to hydrochloride.

In this way, 3-[2-(4-hydroxyphenoxy)-ethylamino]-1-(o-methylphenoxy)-propanol-2 was obtained. HCl. Melting point 150°C. Example_el_21_ (method_g)

1-.0 g of 3-o-methylphenoxy-1-[ 2-(4-hydroxyphenoxy)-ethylamino]-propanone-2 was dissolved in 25 ml of methanol and dissolve

ning cooled to 0°C in an ice bath. 0.25 g of NaBH 2 was added by hand with stirring first at 0°C for 1 hour and then at room temperature for 0.5 hour. The solution thus formed was evaporated, after which 50 ml of H 2 O were added. The water phase was extracted three times with 50 ml of chloroform, after which the combined chloroform phase was dried and evaporated. The hydrochloride was precipitated from an ether solution of the residue by addition of ether containing HCl. Recrystallization from acetone. The hydrochloride of 3-[2-(4-hydroxyphenoxy)-ethylamino]-1-(o-methylphenoxy)-propanol-2 melted at 150°C.

ExemDel_22_(method_h2

3-[2-(4-hydroxyphenoxy)-ethylamino]-1-(o-allyl-phenoxy).-propanol-2 was prepared according to Example 1 from 1,2-epoxy-1-o-allylphenoxypropane and 2-(4-hydroxyphenoxy )-ethylamine. The hydrochloride was dissolved in ethanol and a Pd/C catalyst was added and the compound hydrogenated until the calculated amount of H2 had been absorbed. After filtration, the filtrate was evaporated to dryness and the residue recrystallized from ethyl acetate. In this way, 3-[2-(4-hydroxyphenoxy)-ethyl-amino]-1-(o-propylphenoxy)-propanol-2 was obtained. HCl.

Eczema gel_23

3-[2-(4-Hydroxyphenoxy)-ethylamino]-1-o-methoxy-ethyl-amino-carbonylmethoxy-phenoxy-propanol-2 was prepared according to example 1, starting from 1,2-epoxy-3-o-methoxyethyl -aminocarbonylmethoxyphenoxypropane and 2-(4-hydroxyphenoxy)ethylamine. Melting point 150°C (HCl). The structure was determined by NMR.

Example..?!!

3[-2-(4-hydroxyphenoxy)-ethylamino]-1-o-cyano-methylphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-(o-cyanomethylphenoxy)-propane and 2-(4-hydroxyphenoxy)-ethylamino as starting material. The melting point of the oxalate is 168°C. The structure was determined by NMR and equivalent weight.

Example_el_25

24.9 g of 1-bromo-2-hydroxy-3-(o-methylphenoxy)-propane was mixed with 14.9 g of 2-(4-hydroxyphenoxy)-ethylamine and 25 ml

isopropanol and the mixture refluxed for 1.5 hours. The solution was evaporated in vacuo. The base formed was dissolved in acetone and the hydrochloride was precipitated by introducing ether, in which HCl was dissolved. The hydrochloride was filtered off and washed with acetonitrile. 3~[2-(4-hydroxyphenoxy)-ethyl-amino]-1-o-methylphenoxypropanol-2 was obtained. Yield 18.6 g (53% of theoretical). Melting point 150°C (HCl).

Biological effects

The Ø-receptor blocking compounds produced according to the invention were examined with regard to their biological properties. All compounds were examined thereby on

an anesthetized cat (males and females weighing 2.5-3.5 kg) pretreated with reserpine (5 mg/kg body weight administered intramuscularly) about 16 hours before the experiment. The animals were treated with reserpine to eliminate the endogenous sympathetic control of heart rate and vascular smooth muscle tone. The cats were anesthetized with pentobarbital (30 mg/kg body weight

was administered i.p.) and ventilated artificially with room air. A bilateral vagotomy was performed in the neck. The blood pressure is obtained from a carotid artery equipped with a catheter and the heart rate recorded from a cardiotachometer controlled by an electrocardiogram (ECG l. Beta-mimetic intrinsic effect on the heart was seen as an increased heart rate after administration of the drug. The porsok compounds were given intravenously in logarithmically increasing doses. They achieved values were plotted on dose-response curves from which the affinity values (ED^Q) were calculated.At the end of each experiment, high doses of iso-prenaline were given in order to achieve maximal heart rate s.var.

The compounds were also examined in non-anesthetized dogs. Beagle dogs were trained to lie still and to be raised to an upright position by placing their forelegs on a table for 2 minutes. Arterial blood pressure was recorded via a blood pressure transducer attached to the dog at heart level. Heart rate was determined from the EKG. All dogs were pre-treated with methylscopolamine to avoid daring effects. The measurements were made before and 15 and 75 minutes after administration

ing of the test compound, first in a supine position for 2 min-

otter and then in an upright position for 2 minutes. The test compounds were given in increasing doses at 2 hour intervals.

pA2 was also measured rat. pA^ is -log of the concentration of an antagonist, which means that the dose of noradrenaline must be doubled in order to achieve the same effect of noradrenaline as was achieved without an antagonist or pA2 = log (dr-l)-log (antagonist)

EDj-q norepinephrine (antagonist)

where dr is the dosage ratio - ==-2 ^

EDr5-n U norepinephrine (control)

and all concentrations are given in mol/l. pA2 is thus a measure of α-receptor effect, since higher pA2 ^ higher α effect.

The experiment shows that they investigated compounds of potent -receptor antagonists with or without - mimetic intrinsic effect. The compound also clearly lowers blood pressure in conscious dogs. The pronounced hypotensive effect on conscious dogs of the new compounds is due to a vasodilating effect in combination with cardiac beta-receptor blockade.

The compounds produced according to the invention

is compared with previously known compounds A-H within the technical area, A-H being a) 1-(2-methoxyphenoxy)-3~(2-(2-methoxyphenoxy)ethylamino)-propanol-2 b) 1-(2-hydroxyphenoxy) -3-(2-(2-Methoxyphenoxy)ethylamino)-propanol-2

c) 1-(2-methylphenoxy)-3-(2-phenylthioethylamino)-propanol-2

d) 1-(2-cyanophenoxy)-3-(2-(4-methylphenylthio)ethylamino-propanol-2 e) 1-(2-cyanophenoxy)-3_(2-(3-methyl-6-chlorophenoxy) -1,1-dimethyl-ethylamino)-propanol-2 f) 1-phenoxy-3-(3-methyl-6-chlorophenoxy)-1,1-dimethylethylamino)-propanol-2 g) 1- ( 2- methylphenoxy )-3'- ( 2 - (4-ethylphenoxy)ethylamino)-propanol - 2 h) 1-(2-ally1phenoxy)-3-(l-meth<y>l-2-( 2-methylphenoxy)ethylamino-propanol-2.

Compounds a-b represent compounds from British Patent No. 902,617.

Compounds c-d represent compounds from British Patent No. 1,433-920.

The compounds e-f represent compounds from Swedish application no. 7600846-5. ^

The compounds g-h represent compounds from Norwegian application no. 752765.

The results achieved are shown in table 1 below.

Claims (1)

1. Analogy method for the preparation of therapeutically active amines of formula wherein R"<*>' means- methyl, ethyl, propyl, cyano, cyanomethyl, or CH3OCH2CH2NHCOCH20-, R2 and R<3> are the same or different and means each hydrogen, hydroxy, methoxy or hydroxymethyl provided that R 2 and R -3 ^ does not both mean hydrogen, as R 2 and/or R<3> means hydroxy, hydrogen or hydroxymethyl when R"*" means methyl, characterized in that a) a compound of formula II in which R"*" has the above meaning, X"*" means a hydroxy group and Z is a reactive, esterified hydroxy group, or X"*" and Z together form an epoxy group, is reacted with an amine of formula 2 3 in which R and R^ have the meaning indicated above, or b). a compound according to formula III in which it has the above meaning is reacted with a compound according to formula 2 3 wherein R , R and Z have the above meaning, or c) a compound according to formula IV in which R''" has the above-mentioned meaning, is reacted with a compound of formula V 12 3 in which Z, X, R and R have the above meaning, or d) a compound of formula IV wherein R<1> has the above meaning, is reacted with a compound of formula VI „2 in which R 2 and R 3 have the meaning given above, or 1 2 e) from a compound according to formula I, in which R , R and R<3> have the meaning given above, and which compound has a cleavable residue attached to the amino group and/or the hydroxy groups, this/these residue(s) are cleaved or f) a Schiff's base according to formula VIII or IX or a cyclic tautomer according to formula X corresponding to the compound according to formula IX 12 3 in which R , R and R have the meaning given above, since the compounds IX and X can be present at the same time, reduced or gl in a compound of formula XI 12 3 where R , R and R have the above meaning, the oxo group is reduced to a hydroxy group, h) in a compound according to formula XII 2 3 where R and R have the same meaning as stated above and 2 1 in which X is a residue which is transferable to R with the same meaning-2 1 ning as above, X is transferred to R, or i) in a compound according to formula Va in which r\ n and Z have the meaning indicated above, is reacted with a compound according to formula IVa wherein R<2 > and R 3 have the above meaning and, if desired, aqueous free bases are transferred in their therapeutically acceptable salt or formed salt is transferred in their free bases.